Distinct p53 genomic binding patterns in normal and cancer-derived human cells

Botcheva, Krassimira; McCorkle, S.; McCombie, W. Richard; Dunn, John J.; Anderson, Carl W.

doi:10.4161/cc.10.24.18383

Cited by 85 publications

(137 citation statements)

References 81 publications

(132 reference statements)

Supporting

Mentioning

118

Contrasting

Unclassified

Order By: Relevance

“…Collectively, these findings confirm that Neat1 is bound and regulated by mouse p53 in multiple settings. These data are consistent with published reports showing that human p53 binds to the NEAT1 locus and activates its expression in human fibroblasts and cancer cell lines (Botcheva et al 2011;Blume et al 2015;Adriaens et al 2016).…”

Section: −/−supporting

confidence: 93%

Neat1 is a p53-inducible lincRNA essential for transformation suppression

et al. 2017

View full text Add to dashboard Cite

The p53 gene is mutated in over half of all cancers, reflecting its critical role as a tumor suppressor. Although p53 is a transcriptional activator that induces myriad target genes, those p53-inducible genes most critical for tumor suppression remain elusive. Here, we leveraged p53 ChIP-seq (chromatin immunoprecipitation [ChIP] combined with high-throughput sequencing) and RNA-seq (RNA sequencing) data sets to identify new p53 target genes, focusing on the noncoding genome. We identify Neat1, a noncoding RNA (ncRNA) constituent of paraspeckles, as a p53 target gene broadly induced by mouse and human p53 in different cell types and by diverse stress signals. Using fibroblasts derived from Neat1 −/− mice, we examined the functional role of Neat1 in the p53 pathway. We found that Neat1 is dispensable for cell cycle arrest and apoptosis in response to genotoxic stress. In sharp contrast, Neat1 plays a crucial role in suppressing transformation in response to oncogenic signals. Neat1 deficiency enhances transformation in oncogene-expressing fibroblasts and promotes the development of premalignant pancreatic intraepithelial neoplasias (PanINs) and cystic lesions in Kras G12D -expressing mice. Neat1 loss provokes global changes in gene expression, suggesting a mechanism by which its deficiency promotes neoplasia. Collectively, these findings identify Neat1 as a p53-regulated large intergenic ncRNA (lincRNA) with a key role in suppressing transformation and cancer initiation, providing fundamental new insight into p53-mediated tumor suppression.

show abstract

Section: −/−supporting

confidence: 93%

Neat1 is a p53-inducible lincRNA essential for transformation suppression

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Fluorescence anisotropy titration has shown that methylation of single CG sites does not directly affect p53 binding (47). However, a genome-wide ChIP study found that, in vivo, p53-bound loci are enriched for hypomethylated DNA compared with adjacent sequences (48). Thus, our in vitro results do not exclude the possibility that DNA methylation in the context of chromatin may affect binding of p53 in vivo.…”

Section: Discussioncontrasting

confidence: 35%

Local Depletion of DNA Methylation Identifies a Repressive p53 Regulatory Region in the NEK2 Promoter

Nabilsi

Ryder

Peraza-Penton

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: NEK2 is a mammalian kinase that promotes centrosome separation during the cell cycle. Results: Agents that demethylate the NEK2 promoter or induce DNA damage repress NEK2 expression in a p53-dependent manner. Conclusion: p53 represses NEK2 expression and protects its binding region from accumulating DNA methylation. Significance: Knowledge regarding novel mechanisms of NEK2 regulation may help inform clinical application of NEK2-based anticancer therapeutics.

show abstract

“…Genome-wide profiling of p53 binding and transcriptional activity has been performed previously and led to several general insights (Wei et al 2006;Smeenk et al 2008Smeenk et al , 2011Lee et al 2010;Botcheva et al 2011;Li et al 2012;Nikulenkov et al 2012). First, p53 binds genes representing a wide variety of functional categories, including cell adhesion and axon guidance, and many of these can also be bound by the p53 family members p63 and p73 (Smeenk et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Global genomic profiling reveals an extensive p53-regulated autophagy program contributing to key p53 responses

Brož¹,

Mello²,

Bieging³

et al. 2013

Genes Dev.

385

335

View full text Add to dashboard Cite

The mechanisms by which the p53 tumor suppressor acts remain incompletely understood. To gain new insights into p53 biology, we used high-throughput sequencing to analyze global p53 transcriptional networks in primary mouse embryo fibroblasts in response to DNA damage. Chromatin immunoprecipitation sequencing reveals 4785 p53-bound sites in the genome located near 3193 genes involved in diverse biological processes. RNA sequencing analysis shows that only a subset of p53-bound genes is transcriptionally regulated, yielding a list of 432 p53-bound and regulated genes. Interestingly, we identify a host of autophagy genes as direct p53 target genes. While the autophagy program is regulated predominantly by p53, the p53 family members p63 and p73 contribute to activation of this autophagy gene network. Induction of autophagy genes in response to p53 activation is associated with enhanced autophagy in diverse settings and depends on p53 transcriptional activity. While p53-induced autophagy does not affect cell cycle arrest in response to DNA damage, it is important for both robust p53-dependent apoptosis triggered by DNA damage and transformation suppression by p53. Together, our data highlight an intimate connection between p53 and autophagy through a vast transcriptional network and indicate that autophagy contributes to p53-dependent apoptosis and cancer suppression.

show abstract

Distinct p53 genomic binding patterns in normal and cancer-derived human cells

Cited by 85 publications

References 81 publications

Neat1 is a p53-inducible lincRNA essential for transformation suppression

Neat1 is a p53-inducible lincRNA essential for transformation suppression

Local Depletion of DNA Methylation Identifies a Repressive p53 Regulatory Region in the NEK2 Promoter

Global genomic profiling reveals an extensive p53-regulated autophagy program contributing to key p53 responses

Contact Info

Product

Resources

About